tbuckley/cabot-search huggingface dataset:
Assessing the Genomic Landscape of Cervical Cancers: Clinical Opportunities and Therapeutic Targets
Authors: Claire F. Friedman, Vignesh Ravichandran, Kathryn Miller, Chad Vanderbilt, Qin Zhou, Alexia Iasonos, Malavika Vivek, Pamela Mishra, Mario M. Leitao, Vance Broach, Yukio Sonoda, Chrisann Kyi, Dmitriy Zamarin, Roisin E. O'Cearbhaill, Jason Konner, Michael F. Berger, Britta Weigelt, Amir Momeni Boroujeni, Kay J. Park, Carol Aghajanian, David B. Solit, Mark T.A. Donoghue
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Tumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer. Experimental Design: Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center – Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records. Results: A total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB &amp;gt;10 mut/Mb), 3 of which were also microsatellite instability–high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at &amp;gt;5 years follow-up. Conclusions: Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.
Health trajectories before initiation of non-invasive ventilation for chronic obstructive pulmonary disease: a French nationwide database analysis
Authors: Jean-Louis Pepin, Pauline Lemeille, Hélène Denis, Anne Josseran, Florent Lavergne, Arnaud Panes, Sébastien Bailly, Alain Palot, Arnaud Prigent
Journal: The Lancet Regional Health - Europe (2023)

Chronic obstructive pulmonary disease (COPD) is the most common indication for long-term domiciliary non-invasive ventilation (NIV) but there is uncertainty in data supporting current guidelines. This study described health trajectories before initiation of at-home NIV in people with COPD, and compared mortality outcomes between groups with different pre-NIV health trajectories. Data were from the French national health insurance reimbursement system database for individuals with COPD aged ≥40 years and ≥1 reimbursement for NIV between 1 January 2015 and 31 December 2019. Common health trajectories were determined using time sequence analysis through K-clustering (TAK analysis). Data from 54,545 individuals were analysed; the population was elderly (median age 70 years) with multiple comorbidities. Four clusters were generated. Cluster 1 (n = 35,975/54,545; 66%) had NIV initiated in ambulatory settings or after the first acute event/exacerbation. Cluster 2 (6653/54,545; 12%) started NIV after ≥2 severe exacerbations in the previous 6 months. Cluster 3 (11,375/54,545; 21%) started NIV after frequent severe COPD-related exacerbations in the previous year. Cluster 4 (652/54,545; 1%) started NIV after many long-lasting severe exacerbations. The four clusters differed in age, sex, comorbidities, pre-NIV investigations, and prescriber/location of NIV initiation. Mortality differed significantly between clusters: highest in Cluster 4 and lowest in Cluster 1. The significant heterogeneity in clinical initiation of NIV probably reflects the current lack of strong evidence and guideline recommendations. Knowledge about the characteristics and outcomes in different clusters should be used to address inequities and facilitate more consistent and personalised use domiciliary NIV in COPD. JLP and SB are supported by the French National Research Agency in the framework of the "Investissements d'avenir" program (ANR-15-IDEX-02) and the "e-health and integrated care and trajectories medicine and MIAI artificial intelligence (ANR-19-P3IA-0003)" Chairs of excellence from the Grenoble Alpes University Foundation. This work was supported by ResMed.
European society of Clinical Microbiology and Infectious Diseases guidelines on diagnosis and treatment of brain abscess in children and adults
Authors: Jacob Bodilsen, Quintino Giorgio D'Alessandris, Hilary Humphreys, Mildred A. Iro, Matthias Klein, Katharina Last, Inmaculada López Montesinos, Pasquale Pagliano, Oğuz Reşat Sipahi, Rafael San-Juan, Pierre Tattevin, Majda Thurnher, Rogelio de J. Treviño-Rangel, Matthijs C. Brouwer
Journal: Clinical Microbiology and Infection (2023)
United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions
Authors: David A. Khan, Elizabeth J. Phillips, John J. Accarino, Alexei Gonzalez-Estrada, Iris M. Otani, Allison Ramsey, Anna Chen Arroyo, Aleena Banerji, Timothy Chow, Anne Y. Liu, Cosby A. Stone, Kimberly G. Blumenthal
Journal: Journal of Allergy and Clinical Immunology (2023)
Single-cell transcriptomics reveals granzyme K–expressing cytotoxic Tfh cells in tertiary lymphoid structures in IgG4-RD
Authors: Ryuichi Aoyagi, Takashi Maehara, Risako Koga, Ryusuke Munemura, Tadashi Tomonaga, Yuka Murakami, Atsushi Doi, Hidetaka Yamamoto, Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura
Journal: Journal of Allergy and Clinical Immunology (2023)
SARS-CoV-2–specific antibody and T-cell immunity in convalescents after infection wave in Beijing in late 2022
Authors: Xuejiao Guan, Qi Huang, Mei Dong, Maozhong Li, Hui Xie, Xiaofeng Wei, Lu Kang, Xue Wang, Aihua Li, Qing Wang, Fang Huang, Quanyi Wang
Journal: Journal of Infection (2023)
Does exercise influence skeletal muscle by modulating mitochondrial functions via regulating MicroRNAs? A systematic review
Authors: Yu-Feng Long, Simon Kwoon-Ho Chow, Can Cui, Ronald Man Yeung Wong, Ning Zhang, Ling Qin, Sheung-Wai Law, Wing-Hoi Cheung
Journal: Ageing Research Reviews (2023)

Sarcopenia is the accelerated loss of muscle mass, strength and function. Mitochondrial dysfunction was related to the progression of sarcopenia; meanwhile, microRNAs were regarded as core roles in regulating mitochondrial function. Physical exercise is a well-accepted approach to attenuate sarcopenia, yet very few studies depict the molecular mechanisms. The aim of this systematic review is to explore the potential relationships among physical exercise, mitochondrial function, and microRNAs, which may give new insight for retarding sarcopenia. A systematic literature search was performed in PubMed, Embase and Web of Science. The keywords were combined as "(microRNA OR miR) AND mitochondri* AND muscle AND exercise" and searched in all fields. PRISMA guidelines were followed. Information was extracted from the included studies for review. In this review, 18 preclinical studies and 5 clinical studies were included. Most of the included studies suggested that effective physical exercise had positive effects on mitochondrial functions by regulating microRNAs. The results showed that 12 microRNAs improved mitochondrial functions, while 18 microRNAs suppressed them. Meanwhile, the results showed that 5 microRNAs improved muscle performance. This systematic review provides an up-to-date sequential overview and highlights the potential relationship among exercise, mitochondrial function, and microRNAs in muscle. Meanwhile, evidence revealed that physical exercise can improve muscle performance by up-regulating mitochondrial functions, especially mitochondrial biogenesis, through modulating microRNAs.
Correction: Method for estimation of apoptotic cell fraction of cytotherapy using in vivo fluorine-19 magnetic resonance: pilot study in a patient with head and neck carcinoma receiving tumor-infiltrating lymphocytes labeled with Perfluorocarbon Nanoemulsion
Journal: Journal for ImmunoTherapy of Cancer (2023)

Correction: Method for estimation of apoptotic cell fraction of cytotherapy using in vivo fluorine-19 magnetic resonance: pilot study in a patient with head and neck carcinoma receiving
Survival Effect of Maximal Cytoreductive Surgery for Advanced Ovarian Carcinoma During the Platinum Era: A Meta-Analysis
Authors: Robert E. Bristow, Rafael S. Tomacruz, Deborah K. Armstrong, Edward L. Trimble, F. J. Montz
Journal: Journal of Clinical Oncology (2023)

To evaluate the relative effect of percent maximal cytoreductive surgery and other prognostic variables on survival among cohorts of patients with advanced-stage ovarian carcinoma treated with platinum-based chemotherapy.
Organ-on-a-chip meets artificial intelligence in drug evaluation
Authors: Shiwen Deng, Caifeng Li, Junxian Cao, Zhao Cui, Jiang Du, Zheng Fu, Hongjun Yang, Peng Chen
Journal: Theranostics (2023)

Drug evaluation has always been an important area of research in the pharmaceutical industry. However, animal welfare protection and other shortcomings of traditional drug development models pose obstacles and challenges to drug evaluation. Organ-on-a-chip (OoC) technology, which simulates human organs on a chip of the physiological environment and functionality, and with high fidelity reproduction organ-level of physiology or pathophysiology, exhibits great promise for innovating the drug development pipeline. Meanwhile, the advancement in artificial intelligence (AI) provides more improvements for the design and data processing of OoCs. Here, we review the current progress that has been made to generate OoC platforms, and how human single and multi-OoCs have been used in applications, including drug testing, disease modeling, and personalized medicine. Moreover, we discuss issues facing the field, such as large data processing and reproducibility, and point to the integration of OoCs and AI in data analysis and automation, which is of great benefit in future drug evaluation. Finally, we look forward to the opportunities and challenges faced by the coupling of OoCs and AI. In summary, advancements in OoCs development, and future combinations with AI, will eventually break the current state of drug evaluation.
Advanced hitchhiking nanomaterials for biomedical applications
Authors: Ying Wang, Shao-Kai Sun, Yang Liu, Zhanzhan Zhang
Journal: Theranostics (2023)

Hitchhiking, a recently developed bio-inspired cargo delivery system, has been harnessed for diverse applications.By leveraging the interactions between nanoparticles and circulatory cells or proteins, hitchhiking enables efficient navigation through the vasculature while evading immune system clearance.Moreover, it allows for targeted delivery of nutrients to tissues, surveillance of the immune system, and pathogen elimination.Various synthetic nanomaterials have been developed to facilitate hitchhiking with circulatory cells or proteins.By combining the advantages of synthetic nanomaterials and circulatory cells or proteins, hitchhiking nanomaterials demonstrate several advantages over conventional vectors, including enhanced circulatory stability and optimized therapeutic efficacy.This review provides an overview of general strategies for hitchhiking, choices of cells and proteins, and recent advances of hitchhiking nanomaterials for biomedical applications.
Nuclear translocation of thioredoxin-1 promotes colorectal cancer development via modulation of the IL-6/STAT3 signaling axis through interaction with STAT3
Authors: Aihua Wu, Daoquan Fang, Yangyang Liu, Xiaomeng Shi, Zuyue Zhong, Baojian Zhou, Lechi Ye, Xuecheng Sun, Lei Jiang
Journal: Theranostics (2023)

Background: Thioredoxin 1 (Trx-1) is a small redox protein predominantly localized in the cytoplasm. Its expression is increased in several cancers, including colorectal cancer (CRC). However, the function of Trx-1 translocation to the nucleus in cancer is not clear. In this study, we investigated the role of Trx-1 nuclear translocation in development of CRC. Methods: Expression of Trx-1 and STAT3 was analyzed by Western blot and immunofluorescence. Endogenous interaction of Trx-1, STAT3, and karyopherin α1 in CRC cells was analyzed by co-immunoprecipitation. Trx-1 and pSTAT3 nuclear staining in human CRC tissues was analyzed by immunohistochemistry. A mouse model of AOM/DSS induced colitis-associated cancer (CAC) was utilized to investigate the antitumor effect of PX-12, a Trx-1 inhibitor. A knockin mouse with the Txn1(KK81-82EE) mutation was generated via CRISPR/Cas9, and CAC was induced in knockin and wild-type mice. Results: Nuclear translocation of Trx-1 was induced by IL-6, and inhibition of this translocation reversed IL-6-induced epithelial-to-mesenchymal transition, invasion and metastasis. Karyopherin α1 was found to specifically mediate IL-6-induced translocation of the Trx-1-pSTAT3 complex into the nucleus. Nuclear Trx-1 expression was closely correlated with lymph node metastasis and distant metastasis in human CRC. In addition, nuclear staining of Trx-1 showed significant positive correlation with nuclear staining of pSTAT3 in human CRC tissues. PX-12, an inhibitor of Trx-1, significantly impaired the activation of STAT3 and suppressed the development of AOM/DSS-induced CAC in mice. Moreover, AOM/DSS-induced nuclear Trx-1 expression was suppressed in Txn1(KK81-82EE) mice, which inhibited STAT3 activation and cancer progression. Conclusions: These results provide new insights into the mechanisms of STAT3 activation triggered by IL-6 and identify nuclear translocation of Trx-1 as a potential therapeutic target for the treatment of CRC and CAC.
Oleic acid-induced metastasis of KRAS/p53-mutant colorectal cancer relies on concurrent KRAS activation and IL-8 expression bypassing EGFR activation
Authors: Chih-Jie Shen, Ren-Hao Chan, Bo-Wen Lin, Nien-Chi Li, Ying-Hsuan Huang, Wen-Chang Chang, Ben-Kuen Chen
Journal: Theranostics (2023)

Background: Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy.Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy.This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53.Methods: The cytokine array analysis determined the up-expression of secreted factors, including IL-8.The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset.Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined.The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo.In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified.Results: In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis.IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions.In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS.The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis.Although KRAS mediated EGF-and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis.The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. Conclusion:The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.
Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms as potential pharmacophores for the design of PSMA-targeted radioligands to reduce off-target uptake in kidneys and salivary glands
Authors: Hsiou-Ting Kuo, Zhengxing Zhang, Chengcheng Zhang, Helen Merkens, Ruiyan Tan, Antonio A. W. L. Wong, Carlos F. Uribe, François Bénard, Kuo-Shyan Lin
Journal: Theranostics (2023)

High kidney and salivary gland uptake is a common feature of prostate-specific membrane antigen (PSMA)-targeted radioligands derived from the lysine-urea-glutamic acid (Lys-urea-Glu) pharmacophore. In this study we investigated if radioligands derived from lysine-urea-2-aminoadipic acid (Lys-urea-Aad), lysine-urea-S-carboxylmethylcysteine (Lys-urea-Cmc) and lysine-urea-O-carboxylmethylserine (Lys-urea-Cms) pharmacophores with/without an albumin binder could retain good PSMA-targeting capability but with minimized kidney and salivary gland uptake. Methods: HTK03177 and HTK03187 were obtained by replacing Aad in the previously reported Lys-urea-Aad-derived HTK03149 with Cmc and Cms, respectively. HTK03170, HTK04048 and HTK04028 were derived from HTK03149, HTK03177 and HTK03187, respectively, with the conjugation of an albumin-binding moiety, 4-(p-methoxyphenyl)butyric acid. In vitro competition binding assays were conducted using PSMA-expressing LNCaP prostate cancer cells and [18F]DCFPyL as the radioligand. Imaging and biodistribution studies of 68Ga-labeled HTK03177 and HTK03187, and 177Lu-labeled HTK03170, HTK04048 and HTK04028 were performed in LNCaP tumor-bearing mice. Radioligand therapy study of [177Lu]Lu-HTK03170 was carried out in LNCaP tumor-bearing mice and [177Lu]Lu-PSMA-617 was used for comparison. Results: The calculated Ki(PSMA) values of Ga-HTK03177, Ga-HTK03187, Lu-HTK03170, Lu-HTK04048 and Lu-HTK04028 were 5.0±2.4, 10.6±2.0, 1.6±0.4, 1.4±1.0 and 13.9±3.2 nM, respectively. PET Imaging and biodistribution studies at 1 h post-injection showed that both [68Ga]Ga-HTK03177 and [68Ga]Ga-HTK03187 had high uptake in LNCaP tumor xenografts (24.7±6.85 and 21.1±3.62 %ID/g, respectively) but minimal uptake in normal organs/tissues including kidneys (7.76±1.00 and 2.83±0.45 %ID/g, respectively) and salivary glands (0.22±0.02 and 0.16±0.02 %ID/g, respectively). SPECT imaging and biodistribution studies showed that the LNCaP tumor uptake of 177Lu-labeled HTK03170, HTK04048 and HTK04028 peaked at 4-24 h post-injection at ~43-65 %ID/g and was relatively sustained over time. Their peaked average uptake in kidneys (≤ 17.4 %ID/g) and salivary glands (≤ 2.92 %ID/g) was lower and continuously reduced over time. Radioligand therapy study showed that compared with [177Lu]Lu-PSMA-617 (37 MBq), a quarter dose of [177Lu]Lu-HTK03170 (9.3 MBq) led to a better median survival (63 vs 90 days). Conclusions: Our data demonstrate that that Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms are promising pharmacophores for the design of PSMA-targeted radioligands especially for radiotherapeutic applications to minimize toxicity to kidneys and salivary glands.
The spatial coexistence of TIGIT/CD155 defines poorer survival and resistance to adjuvant chemotherapy in pancreatic ductal adenocarcinoma
Authors: Heng Ma, Xianlong Chen, Shengwei Mo, Xinxin Mao, Jingci Chen, Yilin Liu, Zhaohui Lu, Shuangni Yu, Jie Chen
Journal: Theranostics (2023)

Background: Targeting emerging T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT)/CD155 axis shows promise for restoring anti-tumor immunity, but its immune phenotypes and prognostic significance in a large cohort of pancreatic ductal adenocarcinoma (PDAC) are limited. Methods: Three seven-color multispectral panels were rationally designed to investigate the protein expression, immune-microenvironmental feature, prognostic value, and the response to adjuvant chemotherapy of TIGIT/CD155 in 272 PDAC specimens using multiplex immunohistochemistry. Results: We revealed low immunogenicity and high heterogeneity of the PDAC immune microenvironment featured by abundant CD3+ T cells and CD68+ macrophages and low infiltration of activated cytotoxic T lymphocytes. TIGIT and CD155 were highly expressed in PDAC tissues compared to paracancerous tissues. Tumor-infiltrating lymphocytes expressing TIGIT were correlated with high densities of CD45RO+ T cells; TIGTI+CD8+ T cells were associated with high infiltration of CD3+CD45RO+FOXP3+. CD155+CK+ were significantly related to high densities of CD3+ and CD3+CD8+CD45RO+ T cells. High positive rates for TIGIT in TCs, CD8+ T cells, and CD155 in macrophages were correlated with poor progression-free and disease-specific survival, respectively, and their clinical significance was correlated with PD-L1 status. Notably, spatial co-existence of TIGIT+CK+ or TIGIT+CD8+ and CD155+CD68+ indicated poor survival and resistance to adjuvant chemotherapy response in patients with PDAC. Conclusion: Our findings suggest that targeting TIGIT/CD155 immunosuppressive axis may guide patient stratification and improve the clinical outcome of PDAC.
Restoration of CPT1A-mediated fatty acid oxidation in mesothelial cells protects against peritoneal fibrosis
Authors: Wenyan Su, Zuoyu Hu, Xiaohong Zhong, Ansheng Cong, Ying Zhang, Zhanmei Zhou, Jianyi Li, Cailing Su, Yujie Huang, Wei Cao
Journal: Theranostics (2023)

Background: Peritoneal dialysis (PD) is limited by gradual fibrotic remodeling in the peritoneum, a process involving profibrotic response of mesothelial cells. However, the role of fatty acid oxidation (FAO) and carnitine palmitoyltransferase 1A (CPT1A) in this process remains unexplored. Methods: FAO and CPT1A expression were characterized in mesothelial cells from patients on long-term PD and from a mouse model of PD using multiple experimental methods, including single-cell sequencing, seahorse assay, real-time quantitative PCR, Western blot, and immunofluorescence staining. Overexpression of CPT1A was achieved in a human mesothelial cell line and in primary mouse mesothelial cells. Finally, genetic and pharmacological manipulations of CPT1A were performed in a mouse model of PD. Results: Herein, FAO and CPT1A expression were reduced in mesothelial cells from patients on long-term PD, which negatively correlated with expression of fibrogenic markers in these cells. This was corroborated in PD mice, as well as in mouse and human mesothelial cells incubated with transforming growth factor (TGF) β1. CPT1A overexpression in mesothelial cells, which prevented TGFβ1-induced suppression of mitochondrial respiration, restored cellular ATP levels and downregulated the expression of fibrogenic markers. Furthermore, restoration of FAO by overexpressing CPT1A in PD mice reversed profibrotic phenotype in mesothelial cells and reduced fibrotic lesions in the peritoneum. Treatment with the CPT1A activator C75 induced similar therapeutic benefit in PD mice. In contrast, inhibition of FAO with a CPT1 inhibitor caused more severe fibrosis in PD mice. Conclusions: A defective FAO is responsible for the profibrotic response of mesothelial cells and thus the peritoneal fibrogenesis. This aberrant metabolic state could be improved by modulating CPT1A in mesothelial cells, suggesting FAO enhancement in mesothelial cells is a potential treatment of peritoneal fibrosis.